The invention is concerned with enhancing immune responses. In particular, it has been discovered that modified C-reactive protein (mCRP) and mutant-mCRP can be used to enhance immune responses to immunogens and to elicit an immune response to haptens.
During injury, invasion of pathogens, or other forms of tissue damage, higher vertebrates implement a cascade of biochemical, immune and inflammatory reactions collectively termed the acute phase response. The inflammation results in an increase in blood flow and the delivery of important factors to the affected site. These factors act to limit microbial growth, reduce tissue damage, and aid in the removal of damaged tissue. The acute phase response is a primitive, nonspecific mechanism which reacts quickly prior to the development of the specific processes of humoral and cellular immunity.
C-reactive protein (CRP) has long been recognized as an important acute phase response protein, and its concentration in serum may increase as much as 1,000-fold during the acute phase response. CRP is a pentamer consisting of five identical subunits, each having a molecular weight of about 23,500. The pentameric form of CRP is sometimes referred to as xe2x80x9cnative CRP.xe2x80x9d
In about 1983, another form of CRP was discovered which is referred to as xe2x80x9cmodified-CRPxe2x80x9d or xe2x80x9cmCRP.xe2x80x9d The formation of mCRP from native CRP involves the dissociation of native CRP into its subunits which also undergo a change in conformation. As a result, mCRP expresses antigenicity which is distinct from that of native CRP (referred to as xe2x80x9cneo-CRP antigenicityxe2x80x9d), and antibodies are available which can distinguish mCRP from native CRP (see, e.g., U.S. Pat. No. 5,272,258 and Potempa et al., Mol. Immunol., 24, 531-541 (1987)). The conversion of native CRP into mCRP is irreversible (the subunits do not reassemble into native CRP). Kresl et al., Int""l J. Biochem. Cell Biol., 30, 1415-1426 (1998).
It has been reported that mCRP can influence the development of monocyte cytotoxicity, improve the accessory cell function of monocytes, potentiate aggregated IgG-induced phagocytic cell oxidative metabolism, and increase the production of interleukin-1, prostaglandin E and lipoxygenase products by monocytes. Potempa et al., Protides Biol. Fluids, 34, 287-290 (1987); Potempa et al., Inflammation, 12, 391-405 (1988); Potempa et al., Proc. Amer. Acad. Cancer Res., 28, 344a (1987); Chu et al., Proc. Amer. Acad. Cancer Res., 28, 344a (1987); Zeller et al., Fed. Proc., 46, 1033a (1987); Chu et al., Proc. Amer. Acad. Cancer Res., 29, 371a (1988). It is also known that mCRP can be used to treat viral infections, bacterial infections, endotoxic shock and cancer. See U.S. Pat. Nos. 5,283,238, 5,405,832, 5,474,904, and 5,585,349. It is further known that mCRP stimulates thrombocytopoiesis and the maturation of megakaryocytes and that it can be used to treat thrombocytopenia. See U.S. Pat. No. 5,547,931. Finally, it is known that mCRP binds immune complexes and aggregated immunoglobulin and can, therefore, be used to remove immune complexes and aggregated immunoglobulin from fluids and to quantitate immune complexes. See U.S. Pat. No. 5,593,897. It should be noted that mCRP differs from native CRP in its biological activities. See, e.g., the patents listed above.
The invention provides a method of enhancing an immune response to an immunogen in an animal. The method comprises administering to the animal an effective amount of the immunogen and an effective amount of a modified C-reactive protein (mCRP) or a mutant-mCRP, as further defined below.
The invention further provides a vaccine comprising an immunogen and an mCRP or a mutant-mCRP in a pharmaceutically-acceptable vehicle. The invention also provides a method of producing this vaccine. The method comprises combining the immunogen and an mCRP or a mutant-mCRP.
The invention further provides a kit for immunizing an animal to an immunogen. The kit may comprise a container holding the immunogen and a container holding an mCRP or a mutant-mCRP. Alternatively, the kit may comprise one container holding both the immunogen and the mCRP or mutant-mCRP.
In addition, the invention provides a method of eliciting an immune response to a hapten in an animal. The method comprises administering to the animal an effective amount of the hapten in association with an effective amount of an mCRP or a mutant-mCRP.
The invention further provides a vaccine comprising a hapten and an mCRP or a mutant-mCRP in a pharmaceutically-acceptable vehicle. The invention also provides a method of producing this vaccine. The method comprises combining the hapten and an mCRP or a mutant-mCRP.
Finally, the invention provides a kit for immunizing an animal to a hapten. The kit comprises a container holding the hapten and the mCRP or the mutant-mCRP.